Skip to main content
Top
Published in: BMC Cardiovascular Disorders 1/2017

Open Access 01-12-2017 | Research article

A novel targeted angiogenesis technique using VEGF conjugated magnetic nanoparticles and in-vitro endothelial barrier crossing

Author: Mark Christopher Arokiaraj

Published in: BMC Cardiovascular Disorders | Issue 1/2017

Login to get access

Abstract

Background

Vascular endothelial growth factor is well known for its angiogenesis potential. The study was performed to determine the possible pro-angiogenic role of magnetic nanoparticles coupled to VEGF in vitro and their capacity to cross an endothelial monolayer. This novel treatment technique for angiogenesis could be potentially useful for therapeutic purposes using magnetic nanoparticles.

Methods

Magnetic nanoparticles (MN) were synthesized and were conjugated with the vascular endothelial growth factor. The particles were tested in vitro in a 2D to 3D culture system. MN was seeded in different positions in relation to an HUVEC spheroid to assess a preferential migration.
To evaluate the MN capacity to cross the endothelial barrier, a confluent monolayer of HUVEC cells was seeded on top of a collagen gel. MN was placed in dissolution on the cell culture media, and the MN position was determined by confocal microscopy for 24 h.

Results

HUVEC spheroids were able to generate a preferential sprouting depending on the MN position. Meanwhile, there was random migration when the MN’s were placed all over the collagen gel and no sprouting when no MN was added. The trans-endothelial migration capacity of the MN was observed after 20 h in culture in the absence of external stimuli.

Conclusion

Here we show in vitro angiogenesis following the distribution of the MN conjugated with growth factors. These nanoparticles could be controlled with a magnet to place them in the ischemic area of interest and speed up vascular recovery. Also, MN has potentials to cross endothelium, opening the doors to a possible intravascular and extravascular treatment.
Appendix
Available only for authorised users
Literature
3.
go back to reference Forsythe JA, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996;16:4604–13.CrossRefPubMedPubMedCentral Forsythe JA, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996;16:4604–13.CrossRefPubMedPubMedCentral
4.
go back to reference Rivard A, et al. Age-dependent defect in vascular endothelial growth factor expression is associated with reduced hypoxia-inducible factor 1 activity. J Biol Chem. 2000;275:29643–7.CrossRefPubMed Rivard A, et al. Age-dependent defect in vascular endothelial growth factor expression is associated with reduced hypoxia-inducible factor 1 activity. J Biol Chem. 2000;275:29643–7.CrossRefPubMed
5.
go back to reference Berse B, Brown LF, Van deWater L, Dvorak HF, Senger DR. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell. 1992;3:211–20.CrossRefPubMedPubMedCentral Berse B, Brown LF, Van deWater L, Dvorak HF, Senger DR. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell. 1992;3:211–20.CrossRefPubMedPubMedCentral
6.
go back to reference Enholm B, et al. Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene. 1997;14:2475–83.CrossRefPubMed Enholm B, et al. Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene. 1997;14:2475–83.CrossRefPubMed
7.
go back to reference Mazure NM, Chen EY, Laderoute KR, Giaccia AJ. Induction of vascular endothelial growth factor by hypoxia is modulated by a Phosphatidylinositol 3-Kinase/Akt signaling pathway in ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element. Blood. 1997;90:3322–31.PubMed Mazure NM, Chen EY, Laderoute KR, Giaccia AJ. Induction of vascular endothelial growth factor by hypoxia is modulated by a Phosphatidylinositol 3-Kinase/Akt signaling pathway in ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element. Blood. 1997;90:3322–31.PubMed
8.
go back to reference Ravi R, et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev. 2000;14:34–44.PubMedPubMedCentral Ravi R, et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev. 2000;14:34–44.PubMedPubMedCentral
9.
go back to reference Couffinhal T, et al. Impaired collateral vessel development associated with reduced expression of vascular endothelial growth factor in ApoE−/− mice. Circulation. 1999;99:3188–98.CrossRefPubMed Couffinhal T, et al. Impaired collateral vessel development associated with reduced expression of vascular endothelial growth factor in ApoE−/− mice. Circulation. 1999;99:3188–98.CrossRefPubMed
11.
go back to reference Losordo D. Therapeutic angiogenesis and Vasculogenesis for ischemic disease: part II: cell-based therapies. Circulation. 2004;109:2692–7.CrossRefPubMed Losordo D. Therapeutic angiogenesis and Vasculogenesis for ischemic disease: part II: cell-based therapies. Circulation. 2004;109:2692–7.CrossRefPubMed
12.
go back to reference Grines C. Angiogenic gene therapy (AGENT) trial in patients with stable angina pectoris. Circulation. 2002;105:1291–7.CrossRefPubMed Grines C. Angiogenic gene therapy (AGENT) trial in patients with stable angina pectoris. Circulation. 2002;105:1291–7.CrossRefPubMed
13.
go back to reference Udelson JE, Dilsizian V, Laham RJ. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 improves stress and rest myocardial perfusion abnormalities in patients with severe symptomatic chronic coronary artery disease. Circulation. 2000;102:1605–10.CrossRefPubMed Udelson JE, Dilsizian V, Laham RJ. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 improves stress and rest myocardial perfusion abnormalities in patients with severe symptomatic chronic coronary artery disease. Circulation. 2000;102:1605–10.CrossRefPubMed
14.
15.
16.
go back to reference Vailhé B, Ronot X, Tracqui P, Usson Y, Tranqui L. In vitro angiogenesis is modulated by the mechanical properties of fibrin gels and is related to αvβ3 integrin localization. In Vitro CellDevBiol Animal. 1997;33:763–73.CrossRef Vailhé B, Ronot X, Tracqui P, Usson Y, Tranqui L. In vitro angiogenesis is modulated by the mechanical properties of fibrin gels and is related to αvβ3 integrin localization. In Vitro CellDevBiol Animal. 1997;33:763–73.CrossRef
17.
18.
19.
go back to reference Liu Z, Kobayashi K, Van Dinther M, Van Heiningen SH, Valdimarsdottir G, van LT SM, Lowik CW, Goumans MJ, Ten DP PE. VEGF and inhibitors of TGFβ type-I receptor kinase synergistically promote blood-vessel formation by inducing α5-integrin expression. J Cell Sci. 2009;122:3294–302.CrossRefPubMed Liu Z, Kobayashi K, Van Dinther M, Van Heiningen SH, Valdimarsdottir G, van LT SM, Lowik CW, Goumans MJ, Ten DP PE. VEGF and inhibitors of TGFβ type-I receptor kinase synergistically promote blood-vessel formation by inducing α5-integrin expression. J Cell Sci. 2009;122:3294–302.CrossRefPubMed
20.
go back to reference Bissell MJ, Hall HG, Parry G. How does the extracellular matrix direct gene expression? J Theor Biol. 1982;99:31–68.CrossRefPubMed Bissell MJ, Hall HG, Parry G. How does the extracellular matrix direct gene expression? J Theor Biol. 1982;99:31–68.CrossRefPubMed
21.
go back to reference Hall HG, Farson DA, Bissell MJ. Lumen formation by epithelial cell lines in response to collagen overlay: a morphogenetic model in culture. Proc Natl Acad Sci U S A. 1982;79:4672–6.CrossRefPubMedPubMedCentral Hall HG, Farson DA, Bissell MJ. Lumen formation by epithelial cell lines in response to collagen overlay: a morphogenetic model in culture. Proc Natl Acad Sci U S A. 1982;79:4672–6.CrossRefPubMedPubMedCentral
22.
go back to reference Phillips P, Birnby L, Narendran A. Hypoxia induces capillary network formation in cultured bovine pulmonary micro-vessel endothelial cells. Am J Physiol. 1995;268:789–800. Phillips P, Birnby L, Narendran A. Hypoxia induces capillary network formation in cultured bovine pulmonary micro-vessel endothelial cells. Am J Physiol. 1995;268:789–800.
23.
go back to reference Bulick A, et al. Impact of endothelial cells and mechanical conditioning on smooth muscle cell extracellular matrix production and differentiation. Tissue Eng Part A. 2009;15:815–25.CrossRefPubMed Bulick A, et al. Impact of endothelial cells and mechanical conditioning on smooth muscle cell extracellular matrix production and differentiation. Tissue Eng Part A. 2009;15:815–25.CrossRefPubMed
25.
go back to reference Desai BJ, Gruber HE, Hanley EN Jr. The influence of Matrigel or growth factor reduced Matrigel on human intervertebral disc cell growth and proliferation. Histol Histopathol. 1999 Apr;14(2):359–68.PubMed Desai BJ, Gruber HE, Hanley EN Jr. The influence of Matrigel or growth factor reduced Matrigel on human intervertebral disc cell growth and proliferation. Histol Histopathol. 1999 Apr;14(2):359–68.PubMed
26.
go back to reference Fu A, Wilson R, Smith B, Mullenix J, Earhart C, Akin D, et al. Fluorescent magnetic Nanoparticles for magnetically enhanced cancer imaging and targeting in living subjects. ACS Nano. 2012;6(8):6862–9.CrossRefPubMedPubMedCentral Fu A, Wilson R, Smith B, Mullenix J, Earhart C, Akin D, et al. Fluorescent magnetic Nanoparticles for magnetically enhanced cancer imaging and targeting in living subjects. ACS Nano. 2012;6(8):6862–9.CrossRefPubMedPubMedCentral
27.
go back to reference Galanzha E, et al. In vivo magnetic enrichment and multiplex photoacoustic detection of circulating tumour cells. Nature Nanotech. 2009;4:855–60.CrossRef Galanzha E, et al. In vivo magnetic enrichment and multiplex photoacoustic detection of circulating tumour cells. Nature Nanotech. 2009;4:855–60.CrossRef
29.
go back to reference Cheng K, et al. Magnetic targeting enhances engraftment and functional benefit of iron-labeled Cardiosphere-derived cells in myocardial infarction. Circ Res. 2010;106:1570–81.CrossRefPubMedPubMedCentral Cheng K, et al. Magnetic targeting enhances engraftment and functional benefit of iron-labeled Cardiosphere-derived cells in myocardial infarction. Circ Res. 2010;106:1570–81.CrossRefPubMedPubMedCentral
30.
go back to reference Namiki Y, et al. A novel magnetic crystal–lipid nanostructure for magnetically guided in vivo gene delivery. Nature Nanotech. 2009;4:598–606.CrossRef Namiki Y, et al. A novel magnetic crystal–lipid nanostructure for magnetically guided in vivo gene delivery. Nature Nanotech. 2009;4:598–606.CrossRef
31.
go back to reference Mannix R, et al. Nanomagnetic actuation of receptor-mediated signal transduction. Nature Nanotech. 2007;3:36–40.CrossRef Mannix R, et al. Nanomagnetic actuation of receptor-mediated signal transduction. Nature Nanotech. 2007;3:36–40.CrossRef
32.
go back to reference Brooks P, et al. Integrin αvβ3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell. 1994;79:1157–64.CrossRefPubMed Brooks P, et al. Integrin αvβ3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell. 1994;79:1157–64.CrossRefPubMed
33.
go back to reference Seifu D, Purnama A, Mequanint K, Mantovani D. Small-diameter vascular tissue engineering. Nat Rev Cardiol. 2013;10:410–21.CrossRefPubMed Seifu D, Purnama A, Mequanint K, Mantovani D. Small-diameter vascular tissue engineering. Nat Rev Cardiol. 2013;10:410–21.CrossRefPubMed
34.
go back to reference Reddy L, Arias J, Nicolas J, Couvreur P. Magnetic Nanoparticles: design and characterization, toxicity and biocompatibility, pharmaceutical and biomedical applications. Chem Rev. 2012;112:5818–78.CrossRefPubMed Reddy L, Arias J, Nicolas J, Couvreur P. Magnetic Nanoparticles: design and characterization, toxicity and biocompatibility, pharmaceutical and biomedical applications. Chem Rev. 2012;112:5818–78.CrossRefPubMed
35.
go back to reference Haisler W, et al. Three-dimensional cell culturing by magnetic levitation. Nat Protoc. 2013;8:1940–9.CrossRefPubMed Haisler W, et al. Three-dimensional cell culturing by magnetic levitation. Nat Protoc. 2013;8:1940–9.CrossRefPubMed
36.
go back to reference Dobson J. Remote control of cellular behaviour with magnetic nanoparticles. Nature Nanotech. 2008;3:139–43.CrossRef Dobson J. Remote control of cellular behaviour with magnetic nanoparticles. Nature Nanotech. 2008;3:139–43.CrossRef
Metadata
Title
A novel targeted angiogenesis technique using VEGF conjugated magnetic nanoparticles and in-vitro endothelial barrier crossing
Author
Mark Christopher Arokiaraj
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cardiovascular Disorders / Issue 1/2017
Electronic ISSN: 1471-2261
DOI
https://doi.org/10.1186/s12872-017-0643-x

Other articles of this Issue 1/2017

BMC Cardiovascular Disorders 1/2017 Go to the issue